Insulin resistance is a major pathophysiologic defect in type 2 diabetes and obesity, while anti-inflammatory M2-like macrophages are important in maintaining normal metabolic homeostasis. Here, we show that M2 polarized bone marrow-derived macrophages (BMDMs) secrete miRNA-containing exosomes (Exos), which improve glucose tolerance and insulin sensitivity when given to obese mice. Depletion of their miRNA cargo blocks the ability of M2 BMDM Exos to enhance insulin sensitivity. We found that miR-690 is highly expressed in M2 BMDM Exos and functions as an insulin sensitizer both in vivo and in vitro. Expressing an miR-690 mimic in miRNA-depleted BMDMs generates Exos that recapitulate the effects of M2 BMDM Exos on metabolic phenotypes. Nadk is a bona fide target mRNA of miR-690, and Nadk plays a role in modulating macrophage inflammation and insulin signaling. Taken together, these data suggest miR-690 could be a new therapeutic insulin-sensitizing agent for metabolic disease.

胰岛素抵抗是 2 型糖尿病和肥胖症的主要病理生理缺陷，而抗炎 M2 样巨噬细胞对维持正常的代谢稳态很重要。在这里，我们展示了 M2 极化的骨髓衍生巨噬细胞 (BMDM) 分泌含有 miRNA 的外泌体 (Exos)，当给予肥胖小鼠时，这些外泌体可改善葡萄糖耐量和胰岛素敏感性。它们的 miRNA 货物的消耗会阻止 M2 BMDM Exos 增强胰岛素敏感性的能力。我们发现 miR-690 在 M2 BMDM Exos 中高度表达，并且在体内和体外都起到胰岛素增敏剂的作用。在 miRNA 耗尽的 BMDM 中表达 miR-690 模拟物会产生 Exos，它概括了 M2 BMDM Exos 对代谢表型的影响。纳德克是 miR-690 的真正靶 mRNA，而Nadk在调节巨噬细胞炎症和胰岛素信号传导中发挥作用。总之，这些数据表明 miR-690 可能是一种新的治疗代谢疾病的胰岛素增敏剂。